Adamantane carboxylic acid esters of phenothiazine



United States Patent Cfilice 3,320,248 Patented May 16, 1967 3,320,248ADAMANTANE CARBOXYLIC ACID ESTERS F PHENOTHIAZINE Jack Bernstein, NewBrunswick, N.J., assignor to Olin Mathieson Chemical Corporation, NewYork, N.Y., a corporation of Virginia No Drawing. Filed July 9, 1965,Ser. No. 470,877 6 Claims. (Cl. 260-243) wherein m is 2 to 7 preferably3, n is 0', l or 2; r is 1 or 2, X is hydrogen, halogen (preferablychloro), trifluoromethyl, lower alkyl, lower alkoxy, lower alkanoyl,lower alkyl mercapto, trifiuoromethylmercapto, lower alkylsulfonyl(preferably methylsulfonyl), and di-lower alkylsulfamyl (preferablydinfethylsulfamyl); Y is adamantyl 3-R-5-R -adamantyl, R and R each ishydrogen, halogen, lower alkyl, lower alkoxy or phenyl.

The preferred compounds of this invention are those wherein X is chloroor trifluoromethyl, especially in the 2-position, Y is adamantyl, m is3, n is 0 and r is 1.

Since the compounds of this invention are especially adapted forparenteral administration, as more fully discussed hereinafter, they arepreferably administered in the form of their free esters. The compounds,however, readily form acid-addition salts, which may be utilized in thepreparation of the free esters or the purification thereof and can alsobe used for parenteral formulations. Acids useful for preparing theacid-addition salts include, inter alia, inorganic acids such as thehydrohalic acids (cg. hydrochloric and hydrobromic acid), sulfuric acid,nitric acid and phosphoric acid, and organic acids such as oxalic,tartaric, citric, pamoic, fumaric, acetic, maleic, and succinic acid.

The compounds of this invention are therapeutically active substanceswhich are utilizable as tranquilizing (or ataractic) and antiemeticagents. These compounds differ from the free hydroxyl derivatives inthat they are significantly longer acting when administered perenterallyand thus, when injected subcutaneously or intramuscularly, for example,in a suitable vehicle, yield a long acting tranquilizing or antiemiticdrug.

The compounds of this invention can be prepared by interacting acompound of the general Formula (II):

( 2)m- N( zCHzO),H

wherein X, m and r are as hereinbefore defined, with an adamantyl acylhalide (preferably acyl chloride) of the formula Y(CH ),,CO-halidewherein Y and m are as hereinbefore defined, the reaction preferablybeing conducted in an organic solvent, such as chloroform, for thereactants. Among the suitable phenothiazine reactants may be mentioned:

l0- [3 -'(2-hydroxyethyl piperazinopropyl] phenothiazine 10- 3-(2-hydroxyethyl) piperazinopropyl] -2-halophenothiazines, such as 10- 3-Z-hydroxyethyl) piperazinopropyl] 2-chlorophenothiazine;

10- 3- (Z-hydroxyethyl piperazinopropyl]-2-trifiuoromethylphenothiazine;

10-[3-(Z-hydroxyalkoxyalkyl)piperazinopropyl]-2- halo-phenothiazines,such as 10- 3-(2-hydroxyethoxyethyl)piperazinopropyl]-2-trifiuoromethylphenothiazine l0- [3- (Z-hydroxyethylpiperazinopropyl] -2- (lower alkyl phenothiazines, such as 10- 3-Z-hydroxyethyl piperazinopropyl] -2-methylphenothiazine 10- 3-(2-hydroxyethyl piperazinopropyl] -2- (lower alkoxy) phenothiazines,such as 10- 3- (2-hydroxyethyl) piperazino pro pyl]-2-methoxyphenothiazine;

l0- 3- Z-hydroxyethyl piperazinopropyl] -2(lower alkanoyl)phenothiazines, such as 10- 3- 2-hydroxyethyl) pi perazinopro pyl]-2-propionylphenothiazine;

10- 3- Z-hydroxyethyl) piperazinopropyl] -2-( lower alkyl mercapto-phenothiazines, such as 10- 3- (Z-hydroxyethyl piperazinopropyl]-2-methylmercaptophenothiazine;

10-[3-(Z-hydroxyethyl)piperazinopropyl]-2-trifluoromethylmercaptophenothiazineand 10-[ (Z-hydroxyethyl) piperazinopropyl]-2-methylsulfonylphenothiazine.

Among the suitable acyl halide reactants may be mentioned thel-adamantanecarboxyl acid chlorides such as l-adamantanecarboxylic acidchloride, 3-methy1-l-adamantanecarboxylic acid chloride,3-fluoro-l-adamantanecarboxylic acid chloride,3-chloro-l-adamantanecarboxylic acid chloride,3-bromo-l-adamantanecarboxylic acid chloride,3-iodo-l-adamantanecarboxylic acid chloride,3-methoxy-l-adamantanecarboxylic acid chloride,3-phenyl-l-adamantanecarboxylic acid chloride,3,5-dimethyl-l-adamantanecarboxylic acid chloride,Z-adamantanecarboxylic acid chloride, l-adamantylacetyl chloride, and 2l -adamantyl) propionyl chloride.

All of the acyl halides described hereinbefore may be prepared byheating an acid of the formula wherein Y and n are as hereinbeforedefined, with two parts by weight, of a thionyl halide, preferablythionyl chloride or thionyl bromide, alone, or in the presence of ananhydrous solvent, such as chloroform or benzene, under reflux for aperiod of up to three hours, concentrating to remove the excess thionylhalide (and any solvent present), and then distilling or recrystallizingto obtain the resultant acyl halide, Y(CH ),,COhalide, wherein Y and nare as hereinbefore defined.

The free bases, when initially formed, can be converted to acid-additionsalts by treatment with the desired acid. This reaction is preferablyconducted in an inert organic solvent under substantially anhydrousconditions by treating the base with the acid, whereby the acid-additionsalt is formed.

To prepare the preferred compositions of this invention, the compoundsof this invention, in the form of their free basic esters or acidaddition salts, are dissolved or suspended in a parenterally acceptableliquid vehicle. For prolonged action, the compounds are formulated in anoil such as peanut oil, sesame oil, cottonseed oil, corn oil, soybeanoil, synthetic glycerol esters of long chain fatty acids, and mixturesof these and other oils; the com pound preferably being present in aconcentration to give about 20 mg. to about 300 mg. of the compound perml. The preferable route of administration of these formulations issubcutaneously or intramuscularly.

The following examples illustrate the invention (all temperatures beingin centigrade).

EXAMPLE 1 1-adamantanecarb0xyIic acid chloride A mixture of 10 grams ofl-adamantanecarboxylic acid and 20 ml. of thionyl chloride is heatedunder reflux for thirty minutes. The excess thionyl chloride is removedby distillation under reduced pressure. Ten ml. of anhydrous benzene isadded to the residue and the solvent is removed by distillation underreduced pressure. The residue crystallizes to a solid mass and is usedwithout further purification.

EMMPLE 2 l-aa'amantanecarboxylic acid esterI0-{3-[4-(2J2ydr0xyethyl)-piperazin0]pr0pyl} 2(trifluoromethyl)phenothiazine A.PREPARATION OF THE 1-ADA).[ANTANECARBOX- YLIC ACID ESTER 0F 10-{3-[4-(2-HYDROXYETHYL)PIPERAZINOJPROPYL} 2 TRIFLUOROMETHYLPHE- NOTHIAZINE, DIHYDROCHLORIDE Toa stirred solution of 30.6 g. ofl0-{3-[4-(2-hydroxyethyl)piperazino]propyl}2-trifluoromethylphenothiazine in 300 ml. of dry chloroform is added,dropwise, 16 g. of l-adamantanecarboxylic acid chloride in 50 ml. of drychloroform. Subsequently, the reaction mixture is stirred and heatedunder reflux for live hours, cooled, and shaken with aqueoushydrochloric acid. The dried chloroform solution is concentrated toabout 50 ml., cooled and diluted with about 450 ml. of anhydrous ether.To this cooled solution is added about ml. of ethereal hydrogenchloride. The cooled mixture is filtered and the solid crystallized fromabsolute ethanol and ether to give the product. B.PREPARATION OF THEl-ADAMANTANECARBOX- YLIC ACID ESTER OF 10-{3-[4-(2 HYDROXYETHYL)JZEEERAZINOHROPYL} 2 TRIFLUOROPHENOTHIA- r l v R-substituent Ester3-methyl 3-methyl-l-adamantanecarboxylic. 3-fluoro3-fiuoro-l-adamantanecarboxylic. 3-chloro3-chloro-l-adamantanecarboxylic. 3-bromo 3-bromo-l-adamantanecarboxylic.3-iodo 3-iodo-1-adamantanecarboxylic. 3-methoxy3-methoxy-l-adamantanecarboxylic. 3-phenyl3-phenyl-l-adamantanecarboxylic. 3,5 dimethyl3,5-dimethyl-l-adamantanecarboxylic.

EXAMPLE 3 Z adamantanecarboxylic acid ester of 10 {3 [4 (Z-hydroxyethyl)piperazin0]propyl} 2 trifluoromethylphenotl'ziazine To 89.3 g. ofl0-[3-(2-hydroxyethyl')piperazinopropyl} 2-trifluoromethylphenothiazinein one liter of dry chloroform is added, dropwise, 50 g. of'2-adamantanecarboxylic acid chloride in ml. of dry chloroform. Themixture is then refluxed for two hours and concentrated until free ofchloroform. The residual oil is added to a suspension of 40 g. of sodiumbicarbonate in 400 ml. of ice water and 500 ml. of ether. The mixture isshaken carefully until no further evolution of carbon dioxide occurs,the ether layer is separated, dried and concentrated to give'2-adamantanecarboxylic acid ester of 10 {3 [4 (Z-hydroxyethyl-piperazino pro pyl}-2-trifluoromethylphenothiazine as a pale yellowoil.

EXAMPLE 4 2-adama/ztanecarb0xylic acid ester of 1 0-{3 -'[4-(2'hy1r0xyethyl) piperazino]propyl}-2-triflu0r0methylphenathiazine,salt with 2 moles of maleic acid 12.5 g. of the product obtained inExample 2 (B) is dissolved in 50 ml. of dry chloroform, the solution iscooled, and a saturated solution of 4.46 g. of maleic acid in dryacetone is added dropwise. The precipitated solid is filtered andrecrystallized from dry acetone to give the Z-adamantanecarboxylic acidester of l0-{3-[4-(2-hydroxyethyl) piperazinoJpropyl} 2trifluoromethylphenothiazine, salt with two moles of maleic acid.

EXAMPLE 5 l-adamantylacetic acid ester of 10-{3- [4- (2Izydr0xyetl1yl)piperazino] pr0pyl}-2-(trifluorometlzyl)phenothiazine Following theprocedure set forth in Example 3 but substituting 53 grams ofl-adamantylacetyl chloride for the l-adamantanecarboxylic acid chloridethere is obtained the l-adamantylacetic acid ester of 10-{3-[4-(2-hydroxyethyl)piperazino]propyl}-2-(trifiuoromethyl) phenothiazine.

EXAMPLE 6 3-(I-ada/narityl)propionic acid ester of 10-{3-[4-(2hydroxyethyl)-piperazirz0]pr0pyl} 2 (trifluoromethyl)- phenothiazineA.-3-(1-ADAMANTYL) PROPIONIC ACID Following the procedure of Example 1but substituting 3-(l-adamantyl)propionic acid for the l-adamantanecar-.boxylic acid there is obtained 3-(l-adamantyl)propionyl chloride.

C-.3-(l-ADAMANTYLPROPIONIC ACID ESTER OF 10-(3-[4-(2-HYDROXYETHYL)PIPERAZINO]PROPYL)-2-(TRI- FLUOROMETHYL)PHENOTHIAZINE Following the procedure of Example 2 but substituting anequivalent amount of 3-(l-adamantyl)propionyl chlo ride forl-adamantanecarboxylic acid chloride there is obt-ained the3-(l-adamantyl)propionic acid ester of 10-{3- [4 (2hydroxyethyl)piperazino1propyl} 2 (trifluoromethyl phenothiazine.

EXAMPLE 7 1-adaniaritanecarboxylic acid ester of 10-{3 [4 (2hydroxyethoxyethyl)piperazino]propyl} 2 (trifluoromethyl)phenothiazineFollowing the procedure of Example 2 but substituting an equivalentamount of 10-{3-[4-(2-hydroxyethoxyethyl)piperazino]propyl}-2 7(trifluoromethyl)phenothiazine for the l0-{3-[4-(Z-hydroxyethyl)piperazino]propyl}-2- (trifiuoromethyl)phenothiazine there is obtained the l-adamantanecarboxylic acid ester ofl0-{3 [4 (2 -hydroxyethoxyethyl) piperazino1propyl} 2(trifiuoromethyl)phenothiazine.

Similarly by substituting the -{3-[4-(2-hydroxyethyl)piperazino]propyl}derivatives of the following 2-R substituted phenothiazines, thecorresponding l-adamantanecarboxylic acid esters of the lO-{3-[4-(2-hydroxyethyl) piperazino] propyl} 2 R phenothiazines areobtained.

2-R -substituted 2-R -substituted EXAMPLE 8 Parenteral formulation A 50g. of the l-adamantanecarboxylic acid ester of 10-[3-(Z-hydroxyethyl)piperazinopropyl] 2 trifiuoromethylphenothiazineobtained as in Example 2 is dissolved in 1000 ml. of sesame oil, U.S.P.The solution is sterile filtered and packaged aseptically for parenteraladministration.

EXAMPLE 9 Parenteral formulation B A suspension of 56 g. of micronizedl-adamantanecarboxylic acid ester of10-[3-(2-hydroxyethyl)piperazinopropyl]-2-trifluorornethylphenothiazine,dihydrochloride, prepared as in Example 2, 0.36 g. of lecithin, N.F.,0.18 g. of Tween 80 and 1.68 g. of aluminum monostearate (purified),diluted to 1000 ml. with sesame oil is prepared under sterile conditionsand packaged aseptically for parenteral administration.

EXAMPLE 10 Parenteral formulation C A solution of 50 g. of thel-adamantanecarboxylic acid ester of10-[3-(2-hydroxyethyl)piperazinopropyl]-2 -trifluoromethylphenothiazine,1.5 g. aluminum monostearate (purified), diluted to 1000 ml. with sesameoil, U.S.P., is sterile filtered and packaged aseptically for parenteraladministration.

This invention may be variously otherwise embodied within the scope ofthe appended claims.

What is claimed is:

1. A member selected from the group consisting of a compound of theformula wherein X is selected from the group consisting of hydrogen,halogen, trifluonomethyl, lower alkyl, lower alkoxy, lower alkanoyl,lower alkyl mercapto, trifluoromethylmercapto, lower alkylsulfonyl, anddi-lower alkylsulfamyl; m is an integer from 2 to 7, n is an integerfrom 0 to 2, r is 1 or 2, Y is selected from the group consisting ofadamantyl and 3-R-5-R -adamantyl wherein R and R is a member of thegroup consisting of halogen, lower alkyl, lower alkoxy or phenyl, and apharmaceutically acceptable acid-addition salt thereof.

2. The ester of 10-[3-(Z-hydroxyethyl)piperazinopropyl]-2trifluoromethylphenothiazine and 1 adamantane carboxylic acid.

3. The ester ofl0-[3-(Z-hydroxyethyl)piperazinopropyl]-2-trifluoromethylphenothiazineand l-adamantylacetic acid.

4. The ester of10-[3-(Z-hydroxyethyl)piperazinopropyl]-2-chl0rophenothiazine andl-adamantanecarboxylic acid.

5. The ester of10-[3-(Z-hydroxyethyl)piperazinopropyl]-2-ch1orophenothiazine andl-adamantylacetic acid.

6. The compound of claim 1, wherein the X is in the 2-position.

No references cited.

WALTER A. MODANCE, Primary Examiner. HARRY I. MOATZ, Assistant Examiner.

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THEFORMULA